1-aryl-or 1- alkylsulfonylbenzazole derivatives as 5-hydroxytryptamine-6 ligands

ABSTRACT

The present invention provides a compound of formula I and the use thereof for the therapeutic treatment of disorders relating to or affected by the 5-HT6 receptor.

This application is a continuation-in-part application of co-pendingapplication Ser. No. 10/695,490, filed on Oct. 28, 2003 which is adivisional application of application Ser. No. 10/314,726 filed on Dec.9, 2002 (now U.S. Pat. No. 6,710,069) which is a divisional applicationof application Ser. No. 10/055,365 filed on Jan. 22, 2002 (now U.S. Pat.No. 6,509,357) which application claims the benefit of provisionalapplication Ser. No. 60/263,425, filed on Jan. 23, 2001, the entiredisclosure of each application is hereby incorporated by reference.

BACKGROUND OF THE INVENTION

Various central nervous system disorders such as anxiety, depression,motor disorders, etc., are believed to involve a disturbance of theneurotransmitter 5-hydroxytryptamine (5-HT) or serotonin. Serotonin islocalized in the central and peripheral nervous systems and is known toaffect many types of conditions including psychiatric disorders, motoractivity, feeding behavior, sexual activity, and neuroendocrineregulation among others. The effects of serotonin are regulated by thevarious 5-HT receptor subtypes. Known 5-HT receptors include the 5-HT1family (e.g. 5-HT1A), the 5-HT2 family (e.g. 5-HT2A), 5-HT3, 5-HT4,5-HT5, 5-HT6 and 5-HT7 subtypes.

The recently identified human 5-hydroxytryptamine-6 (5-HT6) receptorsubtype has been cloned, and the extensive distribution of its mRNA hasbeen reported. Highest levels of 5-HT6 receptor mRNA have been observedin the olfactory tubercle, the striatum, nucleus accumbens, dentategyrus and CA1, CA2 and CA3 regions of the hippocampus. Lower levels of5-HT6 receptor mRNA were seen in the granular layer of the cerebellum,several diencephalic nuclei, amygdala and in the cortex. Northern blotshave revealed that 5-HT6 receptor mRNA appears to be exclusively presentin the brain, with little evidence for its presence in peripheraltissues. The high affinity of a number of antipsychotic agents for the5-HT6 receptor, in addition to its mRNA localization in striatum,olfactory tubercle and nucleus accumbens suggests that some of theclinical actions of these compounds may be mediated through thisreceptor. Therefore, 5-HT6 receptor ligands are believed to be ofpotential use in the treatment of certain CNS disorders such as anxiety,depression, epilepsy, obsessive compulsive disorder, attention deficitdisorders, migraine, cognitive memory enhancement (e.g. for thetreatment of Alzheimer's disease), sleep disorders, feeding disorders(e.g. anorexia or bulimia), neurodegenerative disorders (e.g. headtrauma or stroke),panic attacks, withdrawal from drug abuse (e.g.cocaine, ethanol, nicotine or benzodiazepines), schizophrenia, or thelike; or in the treatment of certain gastrointestinal disorders such asirritable bowel syndrome.

Therefore, it is an object of this invention to provide compounds whichare useful as therapeutic agents in the treatment of a variety ofcentral nervous system disorders related to or affected by the 5-HT6receptor.

It is another object of this invention to provide therapeutic methodsand pharmaceutical compositions useful for the treatment of centralnervous system disorders related to or affected by the 5-HT6 receptor.

It is a feature of this invention that the compounds provided may alsobe used to further study and elucidate the 5-HT6 receptor.

These and other objects and features of the invention will become moreapparent by the detailed description set forth hereinbelow.

SUMMARY OF THE INVENTION

The present invention provides a compound of formula I

wherein

-   -   W is SO₂, CO, CONH, CSNH or CH₂;    -   X is CR₇ or N;    -   Y is CR₈ or N with the proviso that when X is N, then Y must be        CR₈;    -   Z is O, SO_(p) or NR₉;    -   R₁ and R₂ are each independently H or C₁-C₆alkyl;    -   n is an integer of 2, 3 or 4;    -   R₃ and R₄ are each independently H, CNR₁₀NR₁₁R₁₂ or a        -   C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,            cycloheteroalkyl, aryl or heteroaryl group each optionally            substituted, or R₃ and R₄ may be taken together with the            atom to which they are attached to form an optionally            substituted 3- to 6-membered ring optionally containing an            additional heteroatom selected from O, N or S;    -   R₅ is H, halogen, CN, OR₁₃, CO₂R₁₄, CONR₁₅R₁₆, CNR₁₇NR₁₈R₁₉,        SO₂NR₂₀R₂₁, SO_(q)R₂₂ or a C₁-C₆alkyl, C₂-C₆alkenyl,        -   C₂-C₆alkynyl, C₃-C₆cycloalkyl, cycloheteroalkyl, phenyl or            heteroaryl group each optionally substituted;    -   m is an integer of 1, 2 or 3;    -   p and q are each independently 0 or an integer of 1 or 2;    -   R₆ is an optionally substituted heteroaryl group or an        optionally substituted 8- to 13-membered bicyclic or tricyclic        ring system having a N atom at the bridgehead and optionally        containing 1, 2 or 3 additional heteroatoms selected from N, O        or S;    -   R₇ and R₈ are each independently H, halogen or a C₁-C₆ alkyl,        aryl, heteroaryl or C₁-C₆alkoxy group each optionally        substituted;    -   R₉ is H or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        -   C₃-C₆cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group            each optionally substituted;    -   R₁₀, R₁₁, R₁₂, R₁₅, R₁₆, R₁₇, R₁₈ and R₁₉ are each independently        H or C₁-C₄alkyl;    -   R₁₃ is H, COR₂₃ or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        aryl or heteroaryl group each optionally substituted;    -   R₁₄ is H or a C₁-C₆alkyl, aryl or heteroaryl group each        optionally substituted;    -   R₂₀ and R₂₁ are each independently H or a C₁-C₆alkyl, aryl or        heteroaryl group each optionally substituted; and    -   R₂₂ and R₂₃ are each independently an optionally substituted        C₁-C₆alkyl, aryl or heteroaryl group; or        a pharmaceutically acceptable salt thereof.

The present invention also provides methods and compositions useful forthe therapeutic treatment of central nervous system disorders related toor affected by the 5-HT6 receptor.

DETAILED DESCRIPTION OF THE INVENTION

The 5-hydroxytryptamine-6 (5-HT6) receptor is one of the most recentreceptors to be identified by molecular cloning. Its ability to bind awide range of therapeutic compounds used in psychiatry, coupled with itsintriguing distribution in the brain has stimulated significant interestin new compounds which are capable of interacting with or affecting saidreceptor. At present, there are no known fully selective agonists.Significant efforts are being made to understand the possible role ofthe 5-HT6 receptor in psychiatry, cognitive dysfunction, motor functionand control, memory, mood and the like. To that end, compounds whichdemonstrate a binding affinity for the 5-HT6 receptor are earnestlysought both as an aid in the study of the 5-HT6 receptor and aspotential therapeutic agents in the treatment of central nervous systemdisorders.

Surprisingly, it has now been found that 1-aryl- or1-alkylsulfonylbenzazole derivatives of formula I demonstrate 5-HT6affinity. Advantageously, said benzazole derivatives may be used aseffective therapeutic agents for the treatment of central nervous system(CNS) disorders associated with or affected by the 5-HT6 receptor.Accordingly, the present invention provides 1-alkyl- or1-arylsulfonylbenzazole derivatives of formula I

wherein

-   -   W is SO₂, CO, CONH, CSNH or CH₂;    -   X is CR₇ or N;    -   Y is CR₈ or N with the proviso that when X is N, then Y must be        CR₈;    -   Z is O, SO_(p) or NR₉;    -   R₁ and R₂ are each independently H or C₁-C₆alkyl;    -   n is an integer of 2, 3 or 4;    -   R₃ and R₄ are each independently H, CNR₁₀NR₁₁R₁₂, or a        -   C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,            cycloheteroalkyl, aryl or heteroaryl group each optionally            substituted, or R₃ and R₄ may be taken together with the            atom to which they are attached to form an optionally            substituted 3- to 6-membered ring optionally containing an            additional heteroatom selected from O, N or S;    -   R₅ is H, halogen, CN, OR₁₃, CO₂R₁₄, CONR₁₅R₁₆, CNR₁₇NR₁₈R₁₉,        SO₂NR₂OR₂₁, SO_(q)R₂₂ or a C₁-C₆alkyl, C₂-C₆alkenyl,        -   C₂-C₆alkynyl, C₃-C₆cycloalkyl, cycloheteroalkyl, phenyl or            heteroaryl group each optionally substituted;    -   m is an integer of 1, 2 or 3;    -   p and q are each independently 0 or an integer of 1 or 2;    -   R₆ is an optionally substituted heteroaryl group or an        optionally substituted 8- to 13-membered bicyclic or tricyclic        ring system having a N atom at the bridgehead and optionally        containing 1, 2 or 3 additional heteroatoms selected from N, O        or S;    -   R₇ and R₈ are each independently H, halogen or a C₁-C₆ alkyl,        aryl, heteroaryl or C₁-C₆alkoxy group each optionally        substituted;    -   R₉ is H or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        -   C₃-C₆cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group            each optionally substituted;    -   R₁₀, R₁₁, R₁₂, R₁₅, R₁₆, R₁₇, R₁₈ and R₁₉ are each independently        H or C₁-C₄alkyl;    -   R₁₃ is H, COR₂₃ or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        aryl or heteroaryl group each optionally substituted;    -   R₁₄ is H or a C₁-C₆alkyl, aryl or heteroaryl group each        optionally substituted;    -   R₂₀ and R₂₁ are each independently H or a C₁-C₆alkyl, aryl or        heteroaryl group each optionally substituted; and    -   R₂₂ and R₂₃ are each independently an optionally substituted        C₁-C₆alkyl, aryl or heteroaryl group; or        a pharmaceutically acceptable salt thereof.

As used in the specification and claims, the term halogen designates Br,Cl, I or F and the term cycloheteroalkyl designates a C₅-C₇cycloalkylring system containing 1 or 2 heteroatoms, which may be the same ordifferent, selected from N, O or S and optionally containing one doublebond. Exemplary of the cycloheteroalkyl ring systems included in theterm as designated herein are the following rings wherein Q is NR, O orS; and R is H or an optional substituent as defined hereinbelow.

Similarly, as used in the specification and claims, the term heteroaryldesignates a C₅-C₁₀ aromatic ring system containing 1 or 2 heteroatoms,which may be the same or different, selected from N, O or S. Suchheteroaryl ring systems include pyrrolyl, azolyl, oxazolyl, thiazolyl,imidazolyl, furyl, thienyl, pyridyl, quinolinyl, isoquinolinyl,indolinyl, benzothienyl, benzofuranyl, benzisoxazolyl and the like; theterm haloalkyl designates a C_(n)H₂₊₁ group having from one to 2n+1halogen atoms which may be the same or different; and the termhaloalkoxy designates an OC_(n)H_(2n+1) group having from one to 2n+1halogen atoms which may be the same or different.

Exemplary of the 8- to 13-membered bicyclic or tricyclic ring systemshaving a N atom at a bridgehead and optionally containing 1, 2 or 3additional heteroatoms selected from N, O or S included in the term asdesignated herein are the following ring systems wherein W is NR, O orS; and R is H or an optional substituent as described hereinbelow:

In the specification and claims, when the terms C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₇cycloalkyl, cycloheteroalkyl, aryl,heteroaryl or 8- to 13-membered bicyclic or tricyclic ring system havinga N atom at the bridgehead are designated as being optionallysubstituted, the substituent groups which are optionally present may beone or more of those customarily employed in the development ofpharmaceutical compounds or the modification of such compounds toinfluence their structure/activity, persistence, absorption, stabilityor other beneficial property. Specific examples of such substituentsinclude halogen atoms, nitro, cyano, thiocyanato, cyanato, hydroxyl,alkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino,formyl, alkoxycarbonyl, carboxyl, alkanoyl, alkylthio, alkylsulphinyl,alkylsulphonyl, carbamoyl, alkylamido, phenyl, phenoxy, benzyl,benzyloxy, heterocyclyl or cycloalkyl groups, preferably halogen atomsor lower alkyl groups. Typically, 0-3 substituents may be present. Whenany of the foregoing substituents represents or contains an alkylsubstituent group, this may be linear or branched and may contain up to12, preferably up to 6, more preferably up to 4 carbon atoms.

Pharmaceutically acceptable salts may be any acid addition salt formedby a compound of formula I and a pharmaceutically acceptable acid suchas phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic,malonic, mandelic, succinic, fumaric, acetic, lactic, nitric, sulfonic,p-toluene sulfonic, methane sulfonic acid or the like.

Preferred compounds of the invention are those compounds of formula Iwherein W is SO₂ or CO. Also preferred are those compounds of formula Iwherein Z is O. Another group of preferred compounds of the inventionare those compounds of formula I wherein n is 2.

More preferred compounds of the invention are those compounds of formulaI wherein W is SO₂; R₁ and R₂ are H; and n is 2. Another group of morepreferred compounds of the invention are those compounds of formula Iwherein W is SO₂; Z is O; X is CR₇; and R₃ and R₄ are taken togetherwith the atom to which they are attached to form a 5- or 6-membered ringoptionally containing one oxygen atom.

Among the preferred compounds of the invention are:

-   1-[(5-chlorothien-2-yl)sulfonyl]-5-[2-(piperidin-1-yl)ethoxy]-1H-indole;-   1-[(4,5-dichlorothien-2-yl)sulfonyl]-5-[2-(piperidin-1-yl)ethoxy]-1H-indole;-   1-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-5-[2-(piperidin-1-yl)ethoxy]-1H-indole;-   1-[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]-5-[2-(piperidin-1-yl)ethoxy]-1H-indole;-   1-[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]-4-[2-(piperidin-1-yl)ethoxy]-1H-indole;-   1-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-4-[2-(piperidin-1-yl)ethoxy]-1H-indazole;-   1-[(4,5-dichlorothien-2-yl)sulfonyl]-4-[2-(piperidin-1-yl)ethoxy]-1H-indazole;-   1-[(5-chlorothien-2-yl)sulfonyl]-4-[2-(piperidin-1-yl)ethoxy]-1H-indazole;-   4-[2-(piperidin-1-yl)ethoxy]-1-(thien-2-ylsulfanyl)-1H-indazole;-   1-[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]-4-[2-(piperidin-1-yl)ethoxy]-1H-indazole;    or    a pharmaceutically acceptable salt thereof.

Compounds of the invention may be prepared using conventional syntheticmethods and, if required, standard separation and isolation techniques.For example, compounds of formula I wherein W is SO₂, R₁ and R₂ are H,and Z is O may be prepared by reacting an hydroxybenzazole intermediateof formula II with a haloalkanoyl of formula III in the presence oftriphenylphosphine and diethyl azodicarboxylate to give the haloalkoxyderivative of formula IV; sulfonating the formula IV derivative to givethe 1-sulfonylbenzazole compound of formula V; and displacing the halogroup of said formula V compound with the appropriate amine to give thedesired compounds of formula Ia. The reaction sequence is illustrated inflow diagram I wherein Hal designates a halogen atom.

Alternatively, compounds of formula Ia may be prepared by reacting theintermediate of formula V with NaN₃ to form the correspondingbenzazolyloxyalkylazide of formula VI; reducing said formula VI azidewith triphenylphosphine to give the formula I compound wherein Z is Oand R₁, R₂, R₃ and R₄ are H(Ib); and optionally alkylating said formulaIb compound to give compounds of formula Ia. The reactions areillustrated in flow diagram II.

Similarly, compounds of formula I wherein W is SO₂ and Z is S may beprepared by utilizing the appropriate benzazolylthiol starting materialand employing essentially the same reaction sequences shown hereinabovein flow diagrams I and II.

Compounds of formula I wherein W is SO₂ and Z is NH (Ic) may be preparedby sulfonating a nitrobenzazole intermediate of formula VII to give thecorresponding 1-sulfonyl derivative of formula VIII; reducing theformula VIII compound to give the corresponding amine of formula IX;reacting said amine with a haloalkylaldehyde of formula X to give thehaloalkylamine derivative of formula XI; and displacing the halo groupof said formula XI derivative with the appropriate amine to give thedesired compounds of formula Ic. The reaction sequence is shown in flowdiagram III.

Compounds of formula I wherein W is CO and Z is O, may be prepared byreacting a compound of formula IV with the appropriate isocyanate orcarbonyl or carbamoyl halide in the presence of a base. Using these andother conventional methods, compounds of formula I may be prepared fromreadily available starting materials.

Advantageously, the inventive compound of formula I may be utilized inthe treatment of central nervous system disorders relating to oraffected by the 5-HT6 receptor such as motor, mood, psychiatric,cognitive, neurodegenerative, or the like disorders. Accordingly, thepresent invention provides a method for the treatment of a disorder ofthe central nervous system (CNS) related to or affected by the 5-HT6receptor in a patient in need thereof which comprises providing saidpatient a therapeutically effective amount of a compound of formula I asdescribed hereinabove. The compounds may be provided by oral orparenteral administration or in any common manner known to be aneffective administration of a therapeutic agent to a patient in needthereof.

The therapeutically effective amount provided in the treatment of aspecific CNS disorder may vary according to the specific condition(s)being treated, the size, age and response pattern of the patient, theseverity of the disorder, the judgment of the attending physician andthe like. In general, effective amounts for daily oral administrationmay be about 0.01 to 1,000 mg/kg, preferably about 0.5 to 500 mg/kg andeffective amounts for parenteral administration may be about 0.1 to 100mg/kg, preferably about 0.5 to 50 mg/kg.

In actual practice, the compounds of the invention are provided byadministering the compound or a precursor thereof in a solid or liquidform, either neat or in combination with one or more conventionalpharmaceutical carriers or excipients. Accordingly, the presentinvention provides a pharmaceutical composition which comprises apharmaceutically acceptable carrier and an effective amount of acompound of formula I as described hereinabove.

Solid carriers suitable for use in the composition of the inventioninclude one or more substances which may also act as flavoring agents,lubricants, solubilizers, suspending agents, fillers, glidants,compression aides, binders, tablet-disintegrating agents orencapsulating materials. In powders, the carrier may be a finely dividedsolid which is in admixture with a finely divided compound of formula I.In tablets, the formula I compound may be mixed with a carrier havingthe necessary compression properties in suitable proportions andcompacted in the shape and size desired. Said powders and tablets maycontain up to 99% by weight of the formula I compound. Solid carrierssuitable for use in the composition of the invention include calciumphosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch,gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Any pharmaceutically acceptable liquid carrier suitable for preparingsolutions, suspensions, emulsions, syrups and elixirs may be employed inthe composition of the invention. Compounds of formula I may bedissolved or suspended in a pharmaceutically acceptable liquid carriersuch as water, an organic solvent, or a pharmaceutically acceptable oilor fat, or a mixture thereof. Said liquid composition may contain othersuitable pharmaceutical additives such as solubilizers, emulsifiers,buffers, preservatives, sweeteners, flavoring agents, suspending agents,thickening agents, coloring agents, viscosity regulators, stabilizers,osmo-regulators, or the like. Examples of liquid carriers suitable fororal and parenteral administration include water (particularlycontaining additives as above, e.g., cellulose derivatives, preferablysodium carboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols, e.g., glycols) or their derivatives,or oils (e.g., fractionated coconut oil and arachis oil). For parenteraladministration the carrier may also be an oily ester such as ethyloleate or isopropyl myristate.

Compositions of the invention which are sterile solutions or suspensionsare suitable for intramuscular, intraperitoneal or subcutaneousinjection. Sterile solutions may also be administered intravenously.Inventive compositions suitable for oral administration may be in eitherliquid or solid composition form.

For a more clear understanding, and in order to illustrate the inventionmore clearly, specific examples thereof are set forth hereinbelow. Thefollowing examples are merely illustrative and are not to be understoodas limiting the scope and underlying principles of the invention in anyway.

Unless otherwise stated, all parts are parts by weight. The terms HPLCand NMR designate high performance liquid chromatography and nuclearmagnetic resonance, respectively. The terms EtOAc and Et₂O designateethyl acetate and diethyl ether, respectively.

Example 1 Preparation of 4-(2-Chloroethoxy)-1H-Indole

A solution of 4-hydroxyindole (3.99 g, 30 mmol), 2-chloroethanol (6.03ml, 90 mmol) and triphenylphosphine (23.6 g, 90 mmol) in tetrahydrofuranis treated with diethyl azodicarboxylate (14.1 ml, 90 mmol) undernitrogen at room temperature, stirred for 2 hr at room temperature andconcentrated in vacuo to give a residue. Cooled diethyl ether is addedto the residue and the solid triphenylphosphine oxide is precipitatedand removed by filtration. The filtrate is concentrated and purified byflash chromatography (silica gel, EtOAc/hexane: 1.5/8.5) to give an oil.After trituration with Et₂O/hexane (1/10), the title compound isobtained as a white solid, 4.8 g (82%) mp 60° C., identified by NMR andmass spectral analyses.

Example 2 Preparation of 4-(2-Chloroethoxy)-1-(phenylsulfonyl)-1H-Indole

A stirred solution of 4-(2-chloroethoxy)-1H-indole (3.4 g, 17.4 mmol) intetrahydrofuran is treated with sodium hydride (60% in mineral oil, 1.04g, 26.1 mmol) under nitrogen at room temperature, stirred for 30minutes, treated with benzenesulfonyl chloride (3.4 mL, 26.1 mmol)stirred at room temperature overnight and treated with saturated NaHCO₃and EtOAc. The resultant phases are separated. The aqueous phase isextracted with EtOAc and the combined organic phase is washedsequentially with H₂O and saturated NaCl, dried over MgSO₄ andconcentrated in vacuo to give a residue. The residue is purified byflash chromatography (silica gel, EtOAc/hexane: 2/8) to give the titlecompound as an off-white solid, 4.94 g (86%), mp 85-87° C., identifiedby NMR and mass spectral analyses.

Example 3 Preparation of2-{[1-(Phenylsulfonyl)-1H-indole-4-yl]oxy}ethylazide

A suspension of 4-(2-chloroethoxy)-1-(phenylsulfonyl)-1H-indole (3.35 g,10 mmol) and sodium azide (1.95 g, 30 mmol) in anhydrousdimethylformamide is stirred under nitrogen for 20 hr at 60° C., pouredinto water and extracted with diethyl ether. The extracts are combined,washed sequentially with 1 N HCl, H₂O and saturated NaCl, dried overMgSO₄ and concentrated in vacuo to afford the title product as anoff-white solid, 3.3 g (96%), identified by NMR and mass spectralanalyses.

Example 4 Preparation of2-{[1-(Phenylsulfonyl)-1H-indole-4-yl]oxy}ethylamine

A mixture of 2-{[1-(phenylsulfonyl)-1H-indole-4-yl]oxy}ethylazide (3.3g, 9.6 mmol) and triphenylphosphine (3.67 g, 14 mmol) in tetrahydrofuranand water is stirred under nitrogen for 24 hr at room temperature andfiltered. The filtrate is concentrated in vacuo and the resultantresidue is purified by flash chromatography (silica gel,EtOAc/MeOH/NH₄OH: 8.5/1.5/0.05) to afford the title compound as anoff-white solid, 2.54 g (80%), mp 71-73° C., identified by NMR and massspectral analyses.

Example 5 Preparation of2-{[1-(Phenylsulfonyl)-1H-indole-4-yl]oxy}ethylamine hydrochloride

A solution of 2-{[1-(phenylsulfonyl)-1H-indole-4-yl]oxy}ethylamine (0.20g, 0.63 mmol) in ethyl acetate is treated with HCl in diethyl ether (1M,0.7 ml) and filtered. The filtercake is dried in vacuo to afford thetitle product as a pink solid, 0.21 g, mp 198-200° C., identified by NMRand mass spectral analyses.

Example 6 Preparation ofN-(2-{[1-(Phenylsulfonyl)-1H-indol-4-yl]oxy}ethyl)tetrahydro-2H-pyran-4-aminehydrochloride

A mixture of 2-{[1-(phenylsulfonyl)-1H-indole-4-yl]oxy}ethylamine (0.316g, 1.0 mmol), tetrahydro-4H-pyran-4-one (0.09 ml, 1.00 mmol) and sodiumtriacetoxyborohydride (0.312 g, 1.4 mmol) in 1,2-dichloroethane istreated with acetic acid (0.06 ml) at room temperature, stirred undernitrogen for 18 hr, quenched with concentrated aqueous NH₄OH and dilutedwith methylene chloride and water. The aqueous layer is separated andextracted with methylene chloride. The organic layer and extracts arecombined, washed with saturated NaCl, dried over Na₂SO₄, andconcentrated in vacuo. The resultant residue is purified by flashchromatography (silica gel, EtOAc/MeOH/NH₄OH: 9/1/0.05) to afford thefree amine of the title product as a clear oil, 0.36 g (90%).

The HCl salt is prepared in HCl and ethyl acetate to give the titleproduct as an off-white solid, mp 229-230° C., identified by NMR andmass spectral analyses.

Examples 7a and 7b Preparation of (a)N,N-Bis(3-methoxybenzyl)-N-(2-{[1-(phenylsulfonyl)-1H-indol-4-yl]oxy}ethylamineand (b)N-(3-methoxybenzyl)-N-(2-{[(phenylsulfonyl)-1H-indol-4-yl]oxy}ethylaminehydrochloride

A mixture of 2-{[1-(phenylsulfonyl)-1H-indole-4-yl]oxy}ethylamine (0.316g, 1.0 mmol), m-anisaldehyde (0.12 ml, 1.0 mmol) and sodiumtriacetoxyborohydride (0.312 g, 1.4 mmol) in 1,2-dichloroethane istreated with acetic acid (0.06 ml) at room temperature, stirred undernitrogen at room temperature for 18 hr, quenched with concentratedaqueous NH₄OH and diluted with methylene chloride and water. The aqueouslayer is separated and extracted with methylene chloride. The organiclayer and extracts are combined and washed with saturated NaCl driedover Na₂SO₄ and concentrated in vacuo to give a residue. The residue ispurified by flash chromatography (silica gel, EtOAc/MeOH/NH₄OH:9.5/0.5/0.05) to afford the free amine of 7a, 0.20 g (36%) as a clearoil and the free amine of 7b, 0.135 g (31%) as a clear oil.

The HCl salt of 7a is prepared in ethyl acetate and anhydrous HCl inether to give the 7a title product as a white solid, mp 194-196° C.,identified by NMR and mass spectral analyses.

The HCl salt of 7b is prepared in ethyl acetate and anhydrous HCl inether to give the 7b title product as a white solid, mp 189-190° C.,identified by NMR and mass spectral analyses.

Example 8 Preparation ofN,N-Dimethyl-N-(2-{[1-phenylsulfonyl)-1H-indol-4-yl]oxy}ethylaminehydrochloride

A mixture of 2-{[1-(phenylsulfonyl)-1H-indole-4-yl]oxy}ethylamine (0.316g, 1.0 mmol), formaldehyde (0.16 ml, 2.0 mmol) and sodiumtriacetoxyborohydride (0.446 g, 2.0 mmol) in 1,2-dichloroethane isstirred under nitrogen at room temperature for 48 hr, quenched withconcentrated aqueous NH₄OH and diluted with methylene chloride. Theaqueous layer is separated and extracted with methylene chloride. Theorganic layer and extracts are combined, washed with saturated NaCl,dried over Na₂SO₄ and concentrated in vacuo. The resultant residue ispurified by flash chromatography (silica gel, EtOAc/MeOH/NH₄OH:9.5/0.5/0.03) to afford the free amine as a white solid, 0.215 g (36%).

The HCl salt is prepared in ethyl acetate and anhydrous HCl in ether togive the title product as a white solid, mp 140-142° C., identified byNMR and mass spectral analyses.

Example 9 Preparation of4-(2-Morpholin-4-ylethoxy)-1-(Phenyl-sulfonyl)-1H-indole hydrochloride

A mixture of 4-(2-chloroethoxy)-1-phenylsulfonyl-1H-indole (0.50 g, 1.5mmol) and morpholine (1.30 ml, 15 mmol) in dimethylformamide (DMF) isstirred under nitrogen at 80° C. for 18 hr, cooled to room temperature,quenched with water and extracted with diethyl ether. The combined etherextracts are washed with saturated sodium chloride, dried over MgSO₄,and concentrated in vacuo. The resultant residue is purified by flashchromatography (silica gel, EtOAc/MeOH/NH₄OH: 9.7/0.5/0.05) to affordthe free amine as a white solid, 0.48 g (83%).

The HCl salt is prepared in ethyl acetate and HCl to afford the titleproduct as a white solid, mp 140-142° C., identified by NMR and massspectral analyses.

Example 10 Preparation of1-(Phenylsulfonyl)-4-(2-piperidin-1-ylethoxy)-1H-indole hydrochloride

A mixture of 4-(2-chloroethoxy)-1-phenylsulfonyl-1H-indole (0.323 g, 1.0mmol) and piperidine (0.99 ml, 10 mmol) in dimethylformamide (DMF) isstirred under nitrogen at 80° C. for 18 hr, cooled to room temperature,quenched with water and extracted with diethyl ether. The ether extractsare combined, washed with saturated sodium chloride, dried over MgSO₄and concentrated in vacuo. The resultant residue is purified by flashchromatography (silica gel, EtOAc/MeOH/NH₄OH: 9.7/0.5/0.05) to affordthe free amine as a light yellow oil 0.34 9 (88%).

The HCl salt is prepared in ethyl acetate and HCl to give the titleproduct as a light yellow solid, mp 131-133° C., identified by NMR andmass spectral analyses.

Examples 11-15 Preparation of1-(Substituted-sulfonyl)-(2-piperidin-1-ylethoxy)-1H-indole Derivatives

Using essentially the same procedures described in Examples 1, 2 and 10and employing the appropriate hydroxyindole substrate and sulfonylchloride reagent, the compounds shown in Table I are obtained andidentified by NMR and mass spectral analyses.

TABLE I

Piperidinyl- ethoxy Ex. Ring mp No. Position R₆ ° C. 11 55-chlorothien-2-yl 222-224 12 5 4,5-dichlorothien-2-yl 222-224 13 56-chloroimidazo[2,1-b][1,3]thiazol-5-yl 60 (foams) 14 55-chloro-3-methyl-1-benzothien-2-yl gum 15 45-chloro-3-methyl-1-benzothien-2-yl 217-219

Example 16 Preparation of 4-(2-Chloroethoxy)-1H-indazole

A stirred solution of 1-acetyl-4-(2-chloroethoxy)-indazole (1.50 g, 6.3mmol) in methanol is treated with hydrochloric acid (6.3 ml, 1.0 M HClin Et₂O, 6.3 mmol) at room temperature, heated at 65° C. under nitrogenfor 18 hr, cooled to room temperature and concentrated in vacuo. Theresultant residue is neutralized with 1 N NaOH (6.0 ml) and diluted withH₂O and ethyl acetate. The phases are separated and the aqueous phase isextracted with ethyl acetate. The combined organic phases are washedwith water and saturated NaCl, dried over Na₂SO₄ and concentrated invacuo to afford the title product (1.2 g) as a yellow solid, identifiedby NMR and mass spectral analyses.

Example 17 Preparation of4-(2-Chloroethoxy)-1-(phenylsulfonyl)-1H-indazole

A stirred solution of 4-(2-chloroethoxy)-1H-indazole (1.1 g, 5.59 mmol)in tetrahydrofuran is treated with NaH (0.335 g, 60% in mineral oil,8.39 mmol) under nitrogen at room temperature, stirred for 30 minutes,treated with benzenesulfonyl chloride (0.86 ml, 6.71 mmol), stirred atroom temperature for 18 hr, quenched with water and diluted with ethylacetate. The phases are separated and the organic phase is washed withwater and brine, dried over MgSO₄ and concentrated in vacuo. Theresultant residue is purified by flash chromatography (silica gel,EtOAc/hexane: 3/7) to give the desired product as a white solid, 1.75 g(93%), mp 102-104° C., identified by NMR and mass spectral analyses.

Example 18 Preparation of1-Phenylsulfonyl)-4-[1-piperidinyl)ethoxy]-1H-indazole hydrochloride

A mixture of 4-(2-chloroethoxy)-1-(phenylsulfonyl)-1H-indazole (0.337 g,1.0 mmol) and piperidine (0.20 ml, 2.0 mmol) in N,N-dimethylformamide(DMF) is stirred under nitrogen at 80° C. for 18 hr, cooled, quenchedwith ice-water and diluted with ethyl acetate. The phases are separated.The aqueous phase is extracted with ethyl acetate. The organic phasesare combined, washed with water and saturated NaCl, dried over MgSO₄ andconcentrated in vacuo to give a yellow oil residue. The residue isdissolved in ethyl acetate, treated with 1 M HCl (1 ml, 1 M HCl in Et₂O)and filtered. The filtercake is dried under vacuum to afford the titleproduct as an off-white solid, 354 mg, mp 87-89° C., identified by NMRand mass spectral analyses.

Example 19 Preparation of2-{[1-Phenylsulfonyl)-1H-indazol-4-yl]oxy}ethylamine hydrochloride

A suspension of 4-(2-chloroethoxy)-1-(phenylsulfonyl)-1H-indazole (0.66g, 1.96 mmol) and sodium azide (0.382 g, 5.87 mmol) inN,N-dimethyl-formamide is stirred under nitrogen at 60° C. for 24 hr,cooled, quenched with 1 N HCl and extracted with ethyl acetate. Thecombined extracts are washed with water and saturated NaCl, dried overNa₂SO₄ and concentrated in vacuo to give a yellow solid residue. Theresidue is dissolved in tetrahydrofuran, treated withtriphenyl-phosphine (0.771 g, 2.94 mmol) and water, stirred at roomtemperature for 18 hr and concentrated in vacuo. The resultant residueis purified by flash chromatography (silica gel, EtOAc/2M NH3 in MeOH:90/10) to give the free amine (0.41 g) as a gum. The gum is dissolved inethyl acetate and treated with anhydrous HCl in ether. The reactionmixture is filtered and the filtercake is air-dried to give the titleproduct as a white solid, mp 201-203° C., identified by NMR and massspectral analyses.

Examples 20-26 Preparation of1-(Substituted-sulfonyl)-4-[2-(1-piperidinyl)-ethoxy]-1H-indazoleDerivatives

Using essentially the same procedures described in Examples 16, 17 and18 and employing the appropriate sulfonyl chloride, the compounds shownin Table II are obtained and identified by NMR and mass spectralanalyses.

TABLE II

Ex. mp No. R₆ ° C. 20 4-nitrophenyl 117-119 21 4-fluorophenyl 122 (dec)22 6-chloroimidazo[2,1-b][1,3]thiazol-5-yl 88-90 234,5-dichlorothien-2-yl 214-216 24 5-chlorothien-2-yl 187-189 25thien-2-yl 172-175 26 5-chloro-3-methyl-1-benzothien-2-yl 216-218

Example 27 Preparation ofN-(2-{[1-Phenylsulfonyl)-1H-indazol-4-yl]oxy}ethyl)tetrahydro-2H-pyran-4-amine

A suspension of 2-{[1-(phenylsulfonyl)-1H-indazol-4-yl]oxy}ethylamine(0.10 g, 0.31 mmol), tetrahydro-4H-pyran-4-one (0.03 ml, 0.31 mmol) andsodium triacetoxyborohydride (0.097 g, 0.43 mmol) in 1,2-dichloroethaneis treated with acetic acid (0.03 ml) at room temperature, allowed tostir under nitrogen at room temperature for 18 hr, quenched with 1N NaOH(2 ml) and diluted with water and a 4:1 mixture of methylenechloride:isopropanol. The phases are separated and the aqueous phase isfurther extracted with a 4:1 mixture of methylene chloride:isopropanol.The organic phases are combined, washed with water and brine, dried overNa₂SO₄ and concentrated in vacuo. The resultant residue is dissolved ina 4:1 mixture of ethyl acetate:isopropanol, treated with anhydrous HClin ether and filtered to obtain the title product as a white solid, mp173-175° C., identified by NMR and mass spectral analyses.

Example 28 Preparation ofN-(2-{[1-Phenylsulfonyl)-1H-indazol-4-yl]oxy}ethyl)tetrahydro-2H-thiopyran-4-aminehydrochloride

Using essentially the same procedures described in Example 17 andsubstituting tetrahydrothiopyran-4-one as the reactant, the titleproduct is obtained as a white solid, mp 182-184° C., identified by NMRand mass spectral analyses.

Example 29 Preparation of4-({4-[2-(1-Piperidinyl)ethoxy]-1H-indazol-1-yl}sulfonyl)aniline

A stirred solution of1-[(4-nitrophenyl)sulfonyl]-4-[2-(1-piperidinyl)ethoxy]1H-indazole (0.39g, 0.91 mol) in methanol is treated with Raney Nickel followed byhydrazine (0.2 ml, 6.3 mmol), stirred at 0° C. for 2 hr and decanted.The catalyst is washed with a methanol:

methylene chloride 3:7 mixture. The washes and supernatant are combinedand concentrated in vacuo. The resultant residue is purified by flashchromatography (silicagel, EtOAc/2M NH₃ in methanol 8:2) to give thetitle product as a white solid, 0.15 g, mp 149-150° C. (dec), identifiedby NMR and mass spectral analyses.

Example 30 Comparative Evaluation of 5-HT6 Binding Affinity of TestCompounds

The affinity of test compounds for the serotonin 5-HT6 receptor isevaluated in the following manner. Cultured Hela cells expressing humancloned 5-HT6 receptors are harvested and centrifuged at low speed(1,000×g) for 10.0 min to remove the culture media. The harvested cellsare suspended in half volume of fresh physiological phosphate bufferedsaline solution and recentrifuged at the same speed. This operation isrepeated. The collected cells are then homogenized in ten volumes of 50mM Tris.HCl (pH 7.4) and 0.5 mM EDTA. The homogenate is centrifuged at40,000×g for 30.0 min and the precipitate is collected. The obtainedpellet is resuspended in 10 volumes of Tris.HCl buffer and recentrifugedat the same speed. The final pellet is suspended in a small volume ofTris.HCl buffer and the tissue protein content is determined in aliquotsof 10-25 μl volumes. Bovine Serum Albumin is used as the standard in theprotein determination according to the method described in Lowry et al.,J. Biol. Chem., 193:265 (1951). The volume of the suspended cellmembranes is adjusted to give a tissue protein concentration of 1.0mg/ml of suspension. The prepared membrane suspension (10 timesconcentrated) is aliquoted in 1.0 ml volumes and stored at −70° C. untilused in subsequent binding experiments.

Binding experiments are performed in a 96 well microtiter plate format,in a total volume of 200 μl. To each well is added the followingmixture: 80.0 μl of incubation buffer made in 50 mM Tris.HCl buffer (pH7.4) containing 10.0 mM MgCl₂ and 0.5 mM EDTA and 20 μl of [³H]-LSD(S.A., 86.0 Ci/mmol, available from Amersham Life Science), 3.0 nM. Thedissociation constant, K_(D) of the [³H]LSD at the human serotonin 5-HT6receptor is 2.9 nM, as determined by saturation binding with increasingconcentrations of [³H]LSD. The reaction is initiated by the finaladdition of 100.0 μl of tissue suspension. Nonspecific binding ismeasured in the presence of 10.0 μM methiothepin. The test compounds areadded in 20.0 μl volume.

The reaction is allowed to proceed in the dark for 120 min at roomtemperature, at which time, the bound ligand-receptor complex isfiltered off on a 96 well unifilter with a Packard Filtermate® 196Harvester. The bound complex caught on the filter disk is allowed to airdry and the radioactivity is measured in a Packard TopCount® equippedwith six photomultiplier detectors, after the addition of 40.0 μlMicroscint®-20 scintillant to each shallow well. The unifilter plate isheat-sealed and counted in a PackardTopCount® with a tritium efficiencyof 31.0%.

Specific binding to the 5-HT6 receptor is defined as the totalradioactivity bound less the amount bound in the presence of 10.0 μMunlabeled methiothepin. Binding in the presence of varyingconcentrations of test compound is expressed as a percentage of specificbinding in the absence of test compound. The results are plotted as log% bound versus log concentration of test compound. Nonlinear regressionanalysis of data points with a computer assisted program Prisms yieldedboth the IC₅₀ and the K_(i) values of test compounds with 95% confidencelimits. A linear regression line of data points is plotted, from whichthe IC₅₀ value is determined and the K_(i)

value is determined based upon the following equation:

K _(i) =IC ₅₀/(1+L/K _(D))

where L is the concentration of the radioactive ligand used and K_(D) isthe dissociation constant of the ligand for the receptor, both expressedin nM.

Using this assay, the following Ki values are determined and compared tothose values obtained by representative compounds known to demonstratebinding to the 5-HT6 receptor. The data are shown in Table III, below.

TABLE III 5-HT6 Binding Ki (nM) Test Compound (Ex. No.)  5 2  6 6  7a94% @ 1 μM*  7b 95% @ 1 μM*  8 4  9 92% @ 1 μM* 10 7 11 51% @ 1 μM* 1265% @ 1 μM* 13 22 14 65% @ 1 μM* 15 71 18 2 19 1 20 76% @ 1 μM* 21 19 222 23 18 24 12 25 8 26 53 27 6 28 11 29 1 Comparative Examples Clozapine6.0 Loxapine 41.4 Bromocriptine 23.0 Methiothepin 8.3 Mianserin 44.2Olanzepine 19.5 *% inhibition at 1 μM concentration

As can be seen from the results set forth above, the compounds of thepresent invention have a high degree of affinity for the serotonin 5-HT6receptor.

1. A compound of formula I

wherein W is SO₂, CO, CONH, CSNH or CH₂; X is CR₇ or N; Y is CR₈ or Nwith the proviso that when X is N, then Y must be CR₈; Z is O, SO_(p) orNR₉; R₁ and R₂ are each independently H or C₁-C₆alkyl; n is an integerof 2, 3 or 4; R₃ and R₄ are each independently H, CNR₁₀NR₁₁R₁₂, or aC₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,cycloheteroalkyl, aryl or heteroaryl group each optionally substituted,or R₃ and R₄ may be taken together with the atom to which they areattached to form an optionally substituted 3- to 6-membered ringoptionally containing an additional heteroatom selected from O, N or S;R₅ is H, halogen, CN, OR₁₃, CO₂R₁₄, CONR₁₅R₁₆, CNR₁₇NR₁₈R₁₉, SO₂NR₂₀R₂₁,SO_(q)R₂₂ or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,cycloheteroalkyl, phenyl or heteroaryl group each optionallysubstituted; m is an integer of 1, 2 or 3; p and q are eachindependently 0 or an integer of 1 or 2; R₆ is an optionally substitutedheteroaryl group or an optionally substituted 8- to 13-membered bicyclicor tricyclic ring system having a N atom at the bridgehead andoptionally containing 1, 2 or 3 additional heteroatoms selected from N,O or S; R₇ and R₈ are each independently H, halogen or a C₁-C₆ alkyl,aryl, heteroaryl or C₁-C₆alkoxy group each optionally substituted; R₉ isH or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;R₁₀, R₁₁, R₁₂, R₁₅, R₁₆, R₁₇, R₁₈ and R₁₉ are each independently H orC₁-C₄alkyl; R₁₃ is H, COR₂₃ or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,aryl or heteroaryl group each optionally substituted; R₁₄ is H or aC₁-C₆alkyl, aryl or heteroaryl group each optionally substituted; R₂₀and R₂₁ are each independently H or a C₁-C₆alkyl, aryl or heteroarylgroup each optionally substituted; and R₂₂ and R₂₃ are eachindependently an optionally substituted C₁-C₆alkyl, aryl or heteroarylgroup; or a pharmaceutically acceptable salt thereof.
 2. The compoundaccording to claim 1 wherein W is SO₂.
 3. The compound according toclaim 1 wherein Z is O.
 4. The compound according to claim 1 wherein nis
 2. 5. The compound according to claim 1 wherein R₆ is an optionallysubstituted thienyl or imidazothiazolyl group.
 6. The compound accordingto claim 1 wherein X is CR₇ and R₅ and R₇ are H.
 7. The compoundaccording to claim 2 wherein R₁ and R₂ are H; Z is O; and n is
 2. 8. Thecompound according to claim 6 wherein W is SO₂; Z is O; and R₃ and R₄are taken together with the atom to which they are attached to form a 5-or 6-membered ring optionally containing one oxygen atom.
 9. Thecompound according to claim 6 selected from the group consisting of:1-[(5-chlorothien-2-yl)sulfonyl]-5-[2-(piperidin-1-yl)ethoxy]-1H-indole;1-[(4,5-dichlorothien-2-yl)sulfonyl]-5-[2-(piperidin-1-yl)ethoxy]-1H-indole;1-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-5-[2-(piperidin-1-yl)ethoxy]-1H-indole;1-[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]-5-[2-(piperidin-1-yl)ethoxy]-1H-indole;1-[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]-4-[2-(piperidin-1-yl)ethoxy]-1H-indole;1-[(6-chloroimidazo[2,1-b][1,3thiazol-5-yl)sulfonyl]-4-[2-(piperidin-1-yl)ethoxy]-1H-indazole;1-[(4,5-dichlorothien-2-yl)sulfonyl]-4-[2-(piperidin-1-yl)ethoxy]-1H-indazole;1-[(5-chlorothien-2-yl)sulfonyl]-4-[2-(piperidin-1-yl)ethoxy]-1H-indazole;4-[2-(piperidin-1-yl)ethoxy]-1-(thien-2-ylsulfanyl)-1H-indazole;1-[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]-4-[2-(piperidin-1-yl)ethoxy]-1H-indazole;and a pharmaceutically acceptable salt thereof.
 10. A method for thetreatment of a disorder of the central nervous system related to oraffected by the 5-HT6 receptor in a patient in need thereof whichcomprises providing to said patient a therapeutically effective amountof a compound of formula I.

wherein W is SO₂, CO, CONH, CSNH or CH₂; X is CR₇ or N; Y is CR₈ or Nwith the proviso that when X is N, then Y must be CR₈; Z is O, SO_(p) orNR₉; R₁ and R₂ are each independently H or C₁-C₆alkyl; n is an integerof 2, 3 or 4; R₃ and R₄ are each independently H, CNR₁₀NR₁₁R₁₂, or aC₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,cycloheteroalkyl, aryl or heteroaryl group each optionally substituted,or R₃ and R₄ may be taken together with the atom to which they areattached to form an optionally substituted 3- to 6-membered ringoptionally containing an additional heteroatom selected from O, N or S;R₅ is H, halogen, CN, OR₁₃, CO₂R₁₄, CONR₁₅R₁₆, CNR₁₇NR₁₈R₁₉, SO₂NR₂OR₂₁,SO_(q)R₂₂ or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,cycloheteroalkyl, phenyl or heteroaryl group each optionallysubstituted; m is an integer of 1, 2 or 3; p and q are eachindependently 0 or an integer of 1 or 2; R₆ is an optionally substitutedheteroaryl group or an optionally substituted 8- to 13-membered bicyclicor tricyclic ring system having a N atom at the bridgehead andoptionally containing 1, 2 or 3 additional heteroatoms selected from N,O or S; R₇ and R₈ are each independently H, halogen or a C₁-C₆ alkyl,aryl, heteroaryl or C₁-C₆alkoxy group each optionally substituted; R₉ isH or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;R₁₀, R₁₁, R₁₂, R₁₅, R₁₆, R₁₇, R₁₈ and R₁₉ are each independently H orC₁-C₄alkyl; R₁₃ is H, COR₂₃ or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,aryl or heteroaryl group each optionally substituted; R₁₄ is H or aC₁-C₆alkyl, aryl or heteroaryl group each optionally substituted; R₂₀and R₂₁ are each independently H or a C₁-C₆alkyl, aryl or heteroarylgroup each optionally substituted; and R₂₂ and R₂₃ are eachindependently an optionally substituted C₁-C₆alkyl, aryl or heteroarylgroup; or a pharmaceutically acceptable salt thereof.
 11. The methodaccording to claim 10 wherein said disorder is a motor disorder, anxietydisorder or cognitive disorder.
 12. The method according to claim 10wherein said disorder is schizophrenia or depression.
 13. The methodaccording to claim 11 wherein said cognitive disorder is attentiondeficit disorder.
 14. The method according to claim 11 wherein saidcognitive disorder is Alzheimer's disease or Parkinson's disease.
 15. Apharmaceutical composition which comprises a pharmaceutically acceptablecarrier and an effective amount of a compound of formula I.

wherein W is SO₂, CO, CONH, CSNH or CH₂; X is CR₇ or N; Y is CR₈ or Nwith the proviso that when X is N, then Y must be CR₈; Z is O, SO_(p) orNR₉; R₁ and R₂ are each independently H or C₁-C₆alkyl; n is an integerof 2, 3 or 4; R₃ and R₄ are each independently H, CNR₁₀NR₁₁R₁₂, or aC₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,cycloheteroalkyl, aryl or heteroaryl group each optionally substituted,or R₃ and R₄ may be taken together with the atom to which they areattached to form an optionally substituted 3- to 6-membered ringoptionally containing an additional heteroatom selected from O, N or S;R₅ is H, halogen, CN, OR₁₃, CO₂R₁₄, CONR₁₅R₁₆, CNR₁₇NR₁₈R₁₉, SO₂NR₂₀R₂₁,SO_(q)R₂₂ or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,cycloheteroalkyl, phenyl or heteroaryl group each optionallysubstituted; m is an integer of 1, 2 or 3; p and q are eachindependently 0 or an integer of 1 or 2; R₆ is an optionally substitutedheteroaryl group or an optionally substituted 8- to 13-membered bicyclicor tricyclic ring system having a N atom at the bridgehead andoptionally containing 1, 2 or 3 additional heteroatoms selected from N,O or S; R₇ and R₈ are each independently H, halogen or a C₁-C₆ alkyl,aryl, heteroaryl or C₁-C₆alkoxy group each optionally substituted; R₉ isH or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;R₁₀, R₁₁, R₁₂, R₁₅, R₁₆, R₁₇, R₁₈ and R₁₉ are each independently H orC₁-C₄alkyl; R₁₃ is H, COR₂₃ or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,aryl or heteroaryl group each optionally substituted; R₁₄ is H or aC₁-C₆alkyl, aryl or heteroaryl group each optionally substituted; R₂₀and R₂₁ are each independently H or a C₁-C₆alkyl, aryl or heteroarylgroup each optionally substituted; and R₂₂ and R₂₃ are eachindependently an optionally substituted C₁-C₆alkyl, aryl or heteroarylgroup; or a pharmaceutically acceptable salt thereof.
 16. Thecomposition according to claim 15 wherein W is SO₂; Z is O; and n is 2.17. The composition according to claim 16 wherein R₆ is an optionallysubstituted thienyl or imidazothiazolyl group.
 18. The compositionaccording to claim 17 wherein X is CR₇ and R₁, R₂, R₅, and R₇ are H. 19.The composition according to claim 15 having a formula I compoundselected from the group consisting of:1-[(5-chlorothien-2-yl)sulfonyl]-5-[2-(piperidin-1-yl)ethoxy]-1H-indole;1-[(4,5-dichlorothien-2-yl)sulfonyl]-5-[2-(piperidin-1-yl)ethoxy]-1H-indole;1-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-5-[2-(piperidin-1-yl)ethoxy]-1H-indole;1-[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]-5-[2-(piperidin-1-yl)ethoxy]-1H-indole;1-[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]-4-[2-(piperidin-1-yl)ethoxy]-1H-indole;1-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-4-[2-(piperidin-1-yl)ethoxy]-1H-indazole;1-[(4,5-dichlorothien-2-yl)sulfonyl]-4-[2-(piperidin-1-yl)ethoxy]-1H-indazole;1-[(5-chlorothien-2-yl)sulfonyl]-4-[2-(piperidin-1-yl)ethoxy]-1H-indazole;4-[2-(piperidin-1-yl)ethoxy]-1-(thien-2-ylsulfonyl)-1H-indazole;1-[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]-4-[2-(piperidin-1-yl)ethoxy]-1H-indazole;and a pharmaceutically acceptable salt thereof.
 20. A method for thepreparation of a compound of formula Ia

wherein X is CR₇ or N; Y is CR₈ or N with the proviso that when X is N,then Y must be CR₈; Z is O, SO_(p) or NR₉; R₁ and R₂ are eachindependently H or C₁-C₆alkyl; n is an integer of 2, 3 or 4; R₃ and R₄are each independently H, CNR₁₀NR₁₁R₁₂, or a C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₃-C₆cycloalkyl, cycloheteroalkyl, aryl or heteroarylgroup each optionally substituted, or R₃ and R₄ may be taken togetherwith the atom to which they are attached to form an optionallysubstituted 3- to 6-membered ring optionally containing an additionalheteroatom selected from O, N or S; R₅ is H, halogen, CN, OR₁₃, CO₂R₁₄,CONR₁₅R₁₆, CNR₁₇NR₁₈R₁₉, SO₂NR₂₀R₂₁, SO_(q)R₂₂ or a C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, cycloheteroalkyl, phenyl orheteroaryl group each optionally substituted; m is an integer of 1, 2 or3; p and q are each independently 0 or an integer of 1 or 2; R₆ is anoptionally substituted heteroaryl group or an optionally substituted 8-to 13-membered bicyclic or tricyclic ring system having a N atom at thebridgehead and optionally containing 1, 2 or 3 additional heteroatomsselected from N, O or S; R₇ and R₈ are each independently H, halogen ora C₁-C₆ alkyl, aryl, heteroaryl or C₁-C₆alkoxy group each optionallysubstituted; R₉ is H or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₃-C₆cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group eachoptionally substituted; R₁₀, R₁₁, R₁₂, R₁₅, R₁₆, R₁₇, R₁₈ and R₁₉ areeach independently H or C₁-C₄alkyl; R₁₃ is H, COR₂₃ or a C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, aryl or heteroaryl group each optionallysubstituted; R₁₄ is H or a C₁-C₆alkyl, aryl or heteroaryl group eachoptionally substituted; R₂₀ and R₂₁ are each independently H or aC₁-C₆alkyl, aryl or heteroaryl group each optionally substituted; andR₂₂ and R₂₃ are each independently an optionally substituted C₁-C₆alkyl,aryl or heteroaryl group which method comprises reacting a compound offormula V′

wherein Hal is Cl, Br or I and X, Y, Z, n, m, R₁, R₂, R₅ and R₆ are asdefined hereinabove with an amine, HNR₃R₄, wherein R₃ and R₄ are definedhereinabove optionally in the presence of a solvent to give the desiredcompound of formula Ia.